A flexible design for advanced Phase I/II clinical trials with continuous efficacy endpoints.

There is growing interest in integrated Phase I/II oncology clinical trials involving molecularly targeted agents (MTA). One of the main challenges of these trials are nontrivial dose-efficacy relationships and administration of MTAs in combination with other agents. While some designs were recently proposed for such Phase I/II trials, the majority of them consider the case of binary toxicity and efficacy endpoints only. At the same time, a continuous efficacy endpoint can carry more information about the agent's mechanism of action, but corresponding designs have received very limited attention in the literature. In this work, an extension of a recently developed information-theoretic design for the case of a continuous efficacy endpoint is proposed. The design transforms the continuous outcome using the logistic transformation and uses an information-theoretic argument to govern selection during the trial. The performance of the design is investigated in settings of single-agent and dual-agent trials. It is found that the novel design leads to substantial improvements in operating characteristics compared to a model-based alternative under scenarios with nonmonotonic dose/combination-efficacy relationships. The robustness of the design to missing/delayed efficacy responses and to the correlation in toxicity and efficacy endpoints is also investigated.